Challenges to the development of vaccines to hepatitis C virus that elicit neutralizing antibodies

Abstract

Despite 20 years of research, a vaccine to prevent hepatitis C virus (HCV) infection has not been developed. A vaccine to prevent HCV will need to induce broadly reactive immunity able to prevent infection by the 7 genetically and antigenically distinct genotypes circulating world-wide. HCV encodes two surface exposed glycoproteins, E1 and E2 that function as a heterodimer to mediate viral entry. Neutralizing antibodies (NAbs) to both E1 and E2 have been described with the major NAb target being E2. The function of E2 is to attach virions to host cells via cell surface receptors that include, but is not limited to, the tetraspanin CD81 and scavenger receptor class B type 1. However, E2 has developed a number of immune evasion strategies to limit the effectiveness of the NAb response and possibly limit the ability of the immune system to generate potent NAbs in natural infection. Hypervariable regions that shield the underlying core domain, subdominant neutralization epitopes and glycan shielding combine to make E2 a difficult target for the immune system. This review summarizes recent information on the role of NAbs to prevent HCV infection, the targets of the NAb response and structural information on glycoprotein E2 in complex with neutralizing antibodies. This new information should provide a framework for the rational design of new vaccine candidates that elicit highly potent broadly reactive NAbs to prevent HCV infection.

Keywords: CD81; glycoprotein E2; immune evasion; neutralizing antibody; viral entry.

FIGURE 1

(A) Schematic of hepatitis C virus glycoproteins E1 and E2 showing the location of conserved glycosylation sites (trees). The transmembrane domains are shown in black and the E2 stem region is indicated with a cylinder. The location of hypervariable regions in E2 is shown in red and the three immunogenic epitopes designated epitopes I, II, and III are underlined. Regions involved in CD81 binding are shown in green with specific contact residues shown in Table 1. (B) Schematic of the E2 core domain according to the designations of Kong et al. (2013). (C) Structure of the E2 core domain colored according to B. (D) Surface representation of C. Purple and teal regions represent the neutralizing face of E2 and overlap with CD81 contact residues shown in E. (E) Surface representation of the E2 core domain with those residues involved in CD81 with their locations colored according to B.

FIGURE 2

Structure of human MAbs in complex with their epitopes. (A) Structure of the paratope of MAb HCV1 in complex with synthetic peptide spanning residues 412–423 within E2 epitope I (pink). Amino acids side chains within the paratope in contact with the antibody epitope are shown as sticks. The antibody heavy chain is colored green and the light chain is in blue and major contact residues within the peptide shown as purple sticks. (B) Structure of the paratope of HC84-1 with its epitope spanning 435–446. Labeled as for A. (C) Structure of the E2 core domain in complex with neutralizing antibody AR3C. E2 is colored in red with the side chains of the amino acid in contact with the antibody shown as sticks. Heavy chain is green and light chain is blue.